2,3-Disubstituted Piperidine Orexin  Receptor Antagonists

ABSTRACT

The present invention is directed to 2,3-disubstituted piperidine amide compounds which are antagonists of orexin receptors, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin receptors are involved.

BACKGROUND OF THE INVENTION

The orexins (hypocretins) comprise two neuropeptides produced in thehypothalamus: the orexin A (OX-A) (a 33 amino acid peptide) and theorexin B (OX-B) (a 28 amino acid peptide) (Sakurai T. et al., Cell,1998, 92, 573-585). Orexins are found to stimulate food consumption inrats suggesting a physiological role for these peptides as mediators inthe central feedback mechanism that regulates feeding behaviour (SakuraiT. et al., Cell, 1998, 92, 573-585). Orexins regulate states of sleepand wakefulness opening potentially novel therapeutic approaches fornarcoleptic or insomniac patients (Chemelli R. M. et al., Cell, 1999,98, 437-451). Orexins have also been indicated as playing a role inarousal, reward, learning and memory (Harris, et al., Trends Neurosci.,2006, 29 (10), 571-577). Two orexin receptors have been cloned andcharacterized in mammals. They belong to the super family of G-proteincoupled receptors (Sakurai T. et al., Cell, 1998, 92, 573-585): theorexin-1 receptor (OX or OX1R) is selective for OX-A and the orexin-2receptor (OX2 or OX2R) is capable to bind OX-A as well as OX-B. Thephysiological actions in which orexins are presumed to participate arethought to be expressed via one or both of OX1 receptor and OX2 receptoras the two subtypes of orexin receptors.

Orexin receptors are found in the mammalian brain and may have numerousimplications in pathologies such as depression; anxiety; addictions;obsessive compulsive disorder; affective neurosis; depressive neurosis;anxiety neurosis; dysthymic disorder; behaviour disorder; mood disorder;sexual dysfunction; psychosexual dysfunction; sex disorder;schizophrenia; manic depression; delirium; dementia; severe mentalretardation and dyskinesias such as Huntington's disease and Tourettesyndrome; eating disorders such as anorexia, bulimia, cachexia, andobesity; addictive feeding behaviors; binge/purge feeding behaviors;cardiovascular diseases; diabetes; appetite/taste disorders; emesis,vomiting, nausea; asthma; cancer; Parkinson's disease; Cushing'ssyndrome/disease; basophile adenoma; prolactinoma; hyperprolactinemia;hypophysis tumour/adenoma; hypothalamic diseases; inflammatory boweldisease; gastric diskinesia; gastric ulcers; Froehlich's syndrome;adrenohypophysis disease; hypophysis disease; adrenohypophysishypofunction; adrenohypophysis hyperfunction; hypothalamic hypogonadism;Kallman's syndrome (anosmia, hyposmia); functional or psychogenicamenorrhea; hypopituitarism; hypothalamic hypothyroidism;hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia;hypothalamic disorders of growth hormone deficiency; idiopathic growthdeficiency; dwarfism; gigantism; acromegaly; disturbed biological andcircadian rhythms; sleep disturbances associated with diseases such asneurological disorders, neuropathic pain and restless leg syndrome;heart and lung diseases, acute and congestive heart failure;hypotension; hypertension; urinary retention; osteoporosis; anginapectoris; myocardinal infarction; ischemic or haemorrhagic stroke;subarachnoid haemorrhage; ulcers; allergies; benign prostatichypertrophy; chronic renal failure; renal disease; impaired glucosetolerance; migraine; hyperalgesia; pain; enhanced or exaggeratedsensitivity to pain such as hyperalgesia, causalgia, and allodynia;acute pain; burn pain; atypical facial pain; neuropathic pain; backpain; complex regional pain syndrome I and II; arthritic pain; sportsinjury pain; pain related to infection e.g. HIV, post-chemotherapy pain;post-stroke pain; post-operative pain; neuralgia; emesis, nausea,vomiting; conditions associated with visceral pain such as irritablebowel syndrome, and angina; migraine; urinary bladder incontinence e.g.urge incontinence; tolerance to narcotics or withdrawal from narcotics;sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet lagsyndrome; and neurodegenerative disorders including nosological entitiessuch as disinhibition-dementia-parkinsonism-amyotrophy complex;pallido-ponto-nigral degeneration; epilepsy; seizure disorders and otherdiseases related to general orexin system dysfunction.

SUMMARY OF THE INVENTION

The present invention is directed to 2,3-disubstituted piperidine amidecompounds which are antagonists of orexin receptors, and which areuseful in the treatment or prevention of neurological and psychiatricdisorders and diseases in which orexin receptors are involved. Theinvention is also directed to pharmaceutical compositions comprisingthese compounds and the use of these compounds and compositions in theprevention or treatment of such diseases in which orexin receptors areinvolved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula I:

wherein:

-   A is selected from the group consisting of phenyl, napthyl and    heteroaryl;-   B is selected from the group consisting of phenyl, napthyl and    heteroaryl;-   R^(1a), R^(1b) and R^(1c) may be absent if the valency of A does not    permit such substitution and are independently selected from the    group consisting of:    -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) —(C═O)_(m)—O_(n)—C₁₋₆alkyl, where m is 0 or 1, n is 0 or 1        (wherein if m is 0 or n is 0, a bond is present) and where the        alkyl is unsubstituted or substituted with one or more        substituents selected from R¹³,    -   (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is        unsubstituted or substituted with one or more substituents        selected from R¹³,    -   (6) —(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted        or substituted with one or more substituents selected from R¹³,    -   (7) —(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted        or substituted with one or more substituents selected from R¹³,    -   (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-napthyl, where        the phenyl or napthyl is unsubstituted or substituted with one        or more substituents selected from R¹³,    -   (9) —(C═O)_(m)—O_(n)-heterocycle, where the heterocycle is        unsubstituted or substituted with one or more substituents        selected from R¹³,    -   (10) —(C═O)_(m)—NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are independently        selected from the group consisting of:        -   (a) hydrogen,        -   (b) C₁₋₆alkyl, which is unsubstituted or substituted with            R¹³,        -   (c) C₃₋₆alkenyl, which is unsubstituted or substituted with            R¹³,        -   (d) C₃₋₆alkynyl, which is unsubstituted or substituted with            R¹³,        -   (e) C₃₋₆cycloalkyl which is unsubstituted or substituted            with R¹³,        -   (f) phenyl, which is unsubstituted or substituted with R¹³,            and        -   (g) heterocycle, which is unsubstituted or substituted with            R¹³,    -   (11) —S(O)₂—NR¹⁰R¹¹,    -   (12) —S(O)_(q)—R¹², where q is 0, 1 or 2 and where R¹² is        selected from the definitions of R¹⁰ and R¹¹,    -   (13) —CO₂H,    -   (14) —CN, and    -   (15) —NO₂;-   R^(2a), R^(2b) and R^(2c) may be absent if the valency of B does not    permit such substitution and are independently selected from the    group consisting of:    -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) —(C═O)_(m)—O_(n)—C₁₋₆alkyl, where the alkyl is unsubstituted        or substituted with one or more substituents selected from R¹³,    -   (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is        unsubstituted or substituted with one or more substituents        selected from R¹³,    -   (6) —(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted        or substituted with one or more substituents selected from R¹³,    -   (7) —(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted        or substituted with one or more substituents selected from R¹³,    -   (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-napthyl, where        the phenyl or napthyl is unsubstituted or substituted with one        or more substituents selected from R¹³,    -   (9) —(C═O)_(m)—O_(n)-heterocycle, where the heterocycle is        unsubstituted or substituted with one or more substituents        selected from R¹³,    -   (10) —(C═O)_(m)—NR¹⁰R¹¹,    -   (11) —S(O)2—NR¹⁰R¹¹,    -   (12) —S(O)_(q)—R¹²,    -   (13) —CO₂H,    -   (14) —CN, and    -   (15) —NO₂;-   R³ is C₁₋₆alkyl or C₃₋₆cycloalkyl, which is unsubstituted or    substituted with one or more substituents selected from R¹³;-   R⁴ and R⁵ are independently selected from hydrogen and C₁₋₆alkyl,    which is unsubstituted or substituted with one or more substituents    selected from R¹³, or R⁴ and R⁵ may be joined together to form a    C₃₋₆cycloalkyl with the carbon atom to which they are attached,    where the cycloalkyl is unsubstituted or substituted with one or    more substituents selected from R¹³;-   R¹³ is selected from the group consisting of:    -   (1) halogen,    -   (2) hydroxyl,    -   (3) —(C═O)_(m)—O_(n)—C₁₋₆alkyl, where the alkyl is unsubstituted        or substituted with one or more substituents selected from R¹⁴,    -   (4) —O_(n)—(C₁₋₃)perfluoroalkyl,    -   (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is        unsubstituted or substituted with one or more substituents        selected from R¹⁴,    -   (6) —(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted        or substituted with one or more substituents selected from R¹⁴,    -   (7) —(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted        or substituted with one or more substituents selected from R¹⁴,    -   (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-napthyl, where        the phenyl or napthyl is unsubstituted or substituted with one        or more substituents selected from R¹⁴,    -   (9) —(C═O)_(m)—O_(n)-heterocycle, where the heterocycle is        unsubstituted or substituted with one or more substituents        selected from R¹⁴,    -   (10) —(C═O)_(m)—NR¹⁰R¹¹,    -   (11) —S(O)₂—NR¹⁰R¹¹,    -   (12) —S(O)_(q)—R¹²,    -   (13) —CO₂H,    -   (14) —CN, and    -   (15) —NO₂;-   R¹⁴ is selected from the group consisting of:    -   (1) hydroxyl,    -   (2) halogen,    -   (3) C₁₋₆alkyl,    -   (4) —C₃₋₆cycloalkyl,    -   (5) —O—C₁₋₆alkyl,    -   (6) —O(C═O)—C₁₋₆alkyl,    -   (7) —NH—C₁₋₆alkyl,    -   (8) phenyl,    -   (9) heterocycle,    -   (10) —CO₂H, and    -   (11) —CN;        or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIa:

wherein B, R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c) and R³ aredefined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIa′:

wherein B, R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c) and R³ aredefined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIa″:

wherein B, R^(1a), R^(1b), R^(1c), R^(2a), R^(2b), R^(2c) and R³ aredefined herein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIb:

wherein B, R^(1a), R^(1b), R^(2a), R^(2b), R^(2c) and R³ are definedherein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIb′:

wherein B, R^(1a), R^(1b), R^(2a), R^(2b), R^(2c) and R³ are definedherein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIb″:

wherein B, R^(1a), R^(1b), R^(2a), R^(2b), R^(2c) and R³ are definedherein; or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds wherein A isselected from the group consisting of: phenyl, pyrazolyl, and thiazolyl.An embodiment of the present invention includes compounds wherein A isphenyl. An embodiment of the present invention includes compoundswherein A is heteroaryl. An embodiment of the present invention includescompounds wherein A is pyrazolyl. An embodiment of the present inventionincludes compounds wherein A is thiazolyl.

An embodiment of the present invention includes compounds wherein B isindependently selected from the group consisting of:

-   -   (1) phenyl,    -   (2) quinoline,    -   (3) isoquinoline,    -   (4) benzoxazole,    -   (5) thienopyridine,    -   (6) pyridine,    -   (7) furan,    -   (8) naphthyridine,    -   (9) benzothiazole, and    -   (10) pyrimidine.

An embodiment of the present invention includes compounds wherein B isquinoline. An embodiment of the present invention includes compoundswherein B is isoquinoline. An embodiment of the present inventionincludes compounds wherein B is pyridine.

An embodiment of the present invention includes compounds whereinR^(1a), R^(1b) and R^(1c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl, phenyl or napthyl,    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (6) heteroaryl, wherein heteroaryl is selected from triazolyl,        oxazolyl, pyrrolyl, imidazolyl, indolyl, pyridyl, and        pyrimidinyl, which is unsubstituted or substituted with halogen,        hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂,    -   (7) phenyl, which is unsubstituted or substituted with halogen,        hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂,    -   (8) —O-phenyl, which is unsubstituted or substituted with        halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂, and    -   (9) —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl), which is        unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,        —O—C₁₋₆alkyl or —NO₂.

An embodiment of the present invention includes compounds whereinR^(1a), R^(1b) and R^(1c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl or napthyl,    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (6) heteroaryl, wherein heteroaryl is selected from triazolyl,        oxazolyl and pyrimidinyl, which is unsubstituted or substituted        with halogen, hydroxyl or C₁₋₆alkyl, and    -   (7) phenyl, which is unsubstituted or substituted with halogen,        hydroxyl or C₁₋₆alkyl.

An embodiment of the present invention includes compounds whereinR^(1a), R^(1b) and R^(1c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) C₁₋₆alkyl,    -   (4) triazolyl,    -   (5) oxazolyl,    -   (6) pyrimidinyl, and    -   (7) phenyl.

An embodiment of the present invention includes compounds wherein R^(1c)is hydrogen and R^(1a) and R^(1b) are independently selected from thegroup consisting of:

-   -   (1) hydrogen,    -   (2) chloro,    -   (3) fluroro,    -   (4) methyl,    -   (5) triazolyl,    -   (6) oxazolyl,    -   (7) pyrimidinyl, and    -   (8) phenyl.

An embodiment of the present invention includes compounds wherein R^(1c)is hydrogen, R^(1b) is hydrogen or methyl, and R^(1a) is selected fromthe group consisting of:

-   -   (1) hydrogen,    -   (2) chloro,    -   (3) fluroro,    -   (4) methyl,    -   (5) triazolyl,    -   (6) oxazolyl,    -   (7) pyrimidinyl, and    -   (8) phenyl.

An embodiment of the present invention includes compounds wherein R^(1c)is hydrogen, R^(1b) is hydrogen or methyl, and R^(1a) is triazolyl. Anembodiment of the present invention includes compounds wherein R^(1c) ishydrogen, R^(1b) is hydrogen or methyl, and R^(1a) is2-(1,2,3-triazolyl).

An embodiment of the present invention includes compounds whereinR^(2a), R^(2b) and R^(2c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl or napthyl,    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (6) heteroaryl, wherein heteroaryl is selected from pyrrolyl,        imidazolyl, indolyl, pyridyl, and pyrimidinyl, which is        unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,        —O—C₁₋₆alkyl or —NO₂,    -   (7) phenyl, which is unsubstituted or substituted with halogen,        hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂,    -   (8) —O-phenyl, which is unsubstituted or substituted with        halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂, and    -   (9) —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl), which is        unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,        —O—C₁₋₆alkyl or —NO₂.

An embodiment of the present invention includes compounds whereinR^(2a), R^(2b) and R^(2c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (5) —O-C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl, and    -   (6) —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl), which is        unsubstituted or substituted with halogen.

An embodiment of the present invention includes compounds whereinR^(2a), R^(2b) and R^(2c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen,    -   (4) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, and    -   (5) —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl), which is        unsubstituted or substituted with halogen.

An embodiment of the present invention includes compounds wherein R^(2c)is hydrogen, and R^(2a) and R^(2b) are independently selected from thegroup consisting of:

-   -   (1) hydrogen,    -   (2) chloro,    -   (3) fluoro,    -   (4) bromo,    -   (5) methoxy,    -   (6) t-butoxy,    -   (7) difluoromethyl, and    -   (8) trifluoromethyl.

An embodiment of the present invention includes compounds wherein R^(2c)is hydrogen, and R^(2a) and R^(2b) are independently selected from thegroup consisting of:

-   -   (1) hydrogen,    -   (2) fluoro, and    -   (3) trifluoromethyl.

An embodiment of the present invention includes compounds wherein R³ isC₁₋₆alkyl or C₃₋₆cycloalkyl. An embodiment of the present inventionincludes compounds wherein R³ is C₁₋₆alkyl. An embodiment of the presentinvention includes compounds wherein R³ is C₃₋₆cycloalkyl. An embodimentof the present invention includes compounds wherein R³ is methyl orethyl. An embodiment of the present invention includes compounds whereinR³ is methyl. An embodiment of the present invention includes compoundswherein R³ is in the trans configuration on the piperidine ring relativeto the heteroaryloxymethyl substituent. An embodiment of the presentinvention includes compounds wherein R³ is in the cis configuration onthe piperidine ring relative to the heteroaryloxymethyl substituent. Anembodiment of the present invention includes compounds wherein R³ is inthe R configuration on the piperidine ring. An embodiment of the presentinvention includes compounds wherein the substituent at the 2-positionof the piperidine ring is in the R configuration. An embodiment of thepresent invention includes compounds wherein heteroaryloxymethyl groupis in the R configuration on the piperidine ring. An embodiment of thepresent invention includes compounds wherein the substituent at the3-position of the piperidine ring is in the R configuration.

An embodiment of the present invention includes compounds wherein R⁴ ishydrogen or C₁₋₆alkyl. An embodiment of the present invention includescompounds wherein R⁴ is hydrogen or methyl. An embodiment of the presentinvention includes compounds wherein R⁴ is hydrogen. An embodiment ofthe present invention includes compounds wherein R⁵ is hydrogen orC₁₋₆alkyl. An embodiment of the present invention includes compoundswherein R⁵ is hydrogen or methyl. An embodiment of the present inventionincludes compounds wherein R⁵ is hydrogen.

Specific embodiments of the present invention include a compound whichis selected from the group consisting of the subject compounds of theExamples herein or a pharmaceutically acceptable salt thereof.

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as “stereoisomers” includingracemates and racemic mixtures, enantiomeric mixtures, singleenantiomers, diastereomeric mixtures and individual diastereomers.Additional asymmetric centers may be present depending upon the natureof the various substituents on the molecule. Each such asymmetric centerwill independently produce two optical isomers and it is intended thatall of the possible optical isomers and diastereomers in mixtures and aspure or partially purified compounds are included within the scope ofthis invention. The present invention is meant to comprehend all suchisomeric forms of these compounds. When bonds to the chiral carbon aredepicted as straight lines in the Formulas of the invention, it isunderstood that both the (R) and (S) configurations of the chiralcarbon, and hence both enantiomers and mixtures thereof, are embracedwithin the Formula. For example, Formula I shows the structure of theclass of compounds without specific stereochemistry. When the compoundsof the present invention contain one chiral center, the term“stereoisomer” includes both enantiomers and mixtures of enantiomers,such as the specific 50:50 mixture referred to as a racemic mixtures.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration. If desired, racemic mixtures ofthe compounds may be separated so that the individual enantiomers areisolated. The separation can be carried out by methods well known in theart, such as the coupling of a racemic mixture of compounds to anenantiomerically pure compound to form a diastereomeric mixture,followed by separation of the individual diastereomers by standardmethods, such as fractional crystallization or chromatography. Thecoupling reaction is often the formation of salts using anenantiomerically pure acid or base. The diasteromeric derivatives maythen be converted to the pure enantiomers by cleavage of the addedchiral residue. The racemic mixture of the compounds can also beseparated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

As appreciated by those of skill in the art, halogen or halo as usedherein are intended to include fluoro, chloro, bromo and iodo.Similarly, C₁₋₆, as in C₁₋₆alkyl is defined to identify the group ashaving 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement,such that C₁₋₈alkyl specifically includes methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and hexyl. A groupwhich is designated as being independently substituted with substituentsmay be independently substituted with multiple numbers of suchsubstituents. The term “heterocycle” as used herein includes bothunsaturated and saturated heterocyclic moieties, wherein the unsaturatedheterocyclic moieties (i.e. “heteroaryl”) include benzoimidazolyl,benzimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl,benzothiazolyl, benzotriazolyl, benzothiophenyl, benzoxazepin,benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl,indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl,oxazolyl, oxazoline, isoxazoline, oxetanyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl,quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl,thiadiazolyl, thiazolyl, thienyl, triazolyl, and N-oxides thereof, andwherein the saturated heterocyclic moieties include azetidinyl,1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl,pyridin-2-onyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl,thiomorpholinyl, and tetrahydrothienyl, and N-oxides thereof.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particular embodiments includethe ammonium, calcium, magnesium, potassium, and sodium salts. Salts inthe solid form may exist in more than one crystal structure, and mayalso be in the form of hydrates. Salts derived from pharmaceuticallyacceptable organic non-toxic bases include salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, and basic ion exchange resins, suchas arginine, betaine, caffeine, choline, N,N′-dibenzylethylene-diamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. Particular embodiments include the citric, hydrobromic,hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.It will be understood that, as used herein, references to the compoundsof Formula I are meant to also include the pharmaceutically acceptablesalts.

Exemplifying the invention is the use of the compounds disclosed in the

Examples and herein. Specific compounds within the present inventioninclude a compound which selected from the group consisting of thecompounds disclosed in the following Examples and pharmaceuticallyacceptable salts thereof and individual enantiomers or diastereomersthereof.

The subject compounds are useful in a method of antagonizing orexinreceptor activity in a patient such as a mammal in need of suchinhibition comprising the administration of an effective amount of thecompound. The present invention is directed to the use of the compoundsdisclosed herein as antagonists of orexin receptor activity. In additionto primates, especially humans, a variety of other mammals can betreated according to the method of the present invention. The presentinvention is directed to a compound of the present invention or apharmaceutically acceptable salt thereof for use in medicine. Thepresent invention is further directed to a use of a compound of thepresent invention or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for antagonizing orexin receptor activity ortreating the disorders and diseases noted herein in humans and animals.

The subject treated in the present methods is generally a mammal, suchas a human being, male or female. The term “therapeutically effectiveamount” means the amount of the subject compound that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought by the researcher, veterinarian, medical doctor or otherclinician. It is recognized that one skilled in the art may affect theneurological and psychiatric disorders by treating a patient presentlyafflicted with the disorders or by prophylactically treating a patientafflicted with the disorders with an effective amount of the compound ofthe present invention. As used herein, the terms “treatment” and“treating” refer to all processes wherein there may be a slowing,interrupting, arresting, controlling, or stopping of the progression ofthe neurological and psychiatric disorders described herein, but doesnot necessarily indicate a total elimination of all disorder symptoms,as well as the prophylactic therapy of the mentioned conditions,particularly in a patient who is predisposed to such disease ordisorder. The terms “administration of” and or “administering a”compound should be understood to mean providing a compound of theinvention or a prodrug of a compound of the invention to the individualin need thereof.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

The utility of the compounds in accordance with the present invention asorexin receptor OX1R and/or OX2R antagonists may be readily determinedwithout undue experimentation by methodology well known in the art,including the “FLIPR Ca²⁺ Flux Assay” (Okumura et al., Biochem. Biophys.Res. Comm. 280:976-981, 2001). In a typical experiment the OX1 and OX2receptor antagonistic activity of the compounds of the present inventionwas determined in accordance with the following experimental method. Forintracellular calcium measurements, Chinese hamster ovary (CHO) cellsexpressing the rat OX1 receptor or the human OX2 receptor, are grown inIscove's modified DMEM containing 2 mM L-glutamine, 0.5 g/ml G418, 1%hypoxanthine-thymidine supplement, 100 U/ml penicillin, 100 ug/mlstreptomycin and 10% heat-inactivated fetal calf serum (FCS). The cellsare seeded at 20,000 cells/well into Becton-Dickinson black 384-wellclear bottom sterile plates coated with poly-D-lysine. All reagents werefrom GIBCO-Invitrogen Corp. The seeded plates are incubated overnight at37° C. and 5% CO₂. Ala-6,12 human orexin-A as the agonist is prepared asa 1 mM stock solution in 1% bovine serum albumin (BSA) and diluted inassay buffer (HBSS containing 20 mM HEPES, 0.1% BSA and 2.5 mMprobenecid, pH7.4) for use in the assay at a final concentration of 70pM. Test compounds are prepared as 10 mM stock solution in DMSO, thendiluted in 384-well plates, first in DMSO, then assay buffer. On the dayof the assay, cells are washed 3 times with 100 ul assay buffer and thenincubated for 60 min (37° C., 5% CO₂) in 60 ul assay buffer containing 1uM Fluo-4AM ester, 0.02% pluronic acid, and 1% BSA. The dye loadingsolution is then aspirated and cells are washed 3 times with 100 ulassay buffer. 30 ul of that same buffer is left in each well. Within theFluorescent Imaging Plate Reader (FLIPR, Molecular Devices), testcompounds are added to the plate in a volume of 25 ul, incubated for 5min and finally 25 ul of agonist is added. Fluorescence is measured foreach well at 1 second intervals for 5 minutes and the height of eachfluorescence peak is compared to the height of the fluorescence peakinduced by 70 pM Ala-6,12 orexin-A with buffer in place of antagonist.For each antagonist, IC50 value (the concentration of compound needed toinhibit 50% of the agonist response) is determined. Alternatively,compound potency can be assessed by a radioligand binding assay(described in Bergman et. al. Bioorg. Med. Chem. Lett. 2008, 18,1425-1430) in which the inhibition constant (K_(i)) is determined inmembranes prepared from CHO cells expressing either the orexin-1 (OX1)or orexin-2 (OX2) receptor. The intrinsic orexin receptor antagonistactivity of a compound which may be used in the present invention may bedetermined by these assays.

In particular, the compounds of the following examples had activity inantagonizing the rat orexin-1 (OX1) receptor and/or the human orexin-2(OX2) receptor in the aforementioned assays, generally with an IC₅₀ ofless than about 50 μM. Many of compounds within the present inventionhad activity in antagonizing the rat orexin-1 (OX1) receptor and/or thehuman orexin-2 (OX2) receptor in the aforementioned assays with an IC₅₀of less than about 100 nM. Compounds of the present invention also haveactivity in the radioligand binding assay, generally with a Ki<100 nMagainst the orexin-1 (OX1) and/or the orexin-2 (OX2) receptor.Additional data is provided in Table 2. Such a result is indicative ofthe intrinsic activity of the compounds in use as antagonists oforexin-1 (OX1) receptor and/or the orexin-2 (OX2) receptor. The presentinvention also includes compounds within the generic scope of theinvention which possess activity as agonists of the orexin-1 (OX1)receptor and/or the orexin-2 (OX2) receptor. With respect to otherpiperidine compounds, the present compounds exhibit unexpectedproperties, such as with respect to increased potency, oralbioavailability, metabolic stability, and/or selectivity. For example,relative to compounds which possess an unsubstituted piperidine ring,the present compounds wherein R³ is substituted such as with a C₁₋₆alkyl or C₃₋₆ cycloalkyl possess unexpectedly greater potency at theorexin-1 (OX1) receptor and/or the orexin-2 (OX2) receptor.

The orexin receptors have been implicated in a wide range of biologicalfunctions. This has suggested a potential role for these receptors in avariety of disease processes in humans or other species. The compoundsof the present invention have utility in treating, preventing,ameliorating, controlling or reducing the risk of a variety ofneurological and psychiatric disorders associated with orexin receptors,including one or more of the following conditions or diseases: sleepdisorders, sleep disturbances, including enhancing sleep quality,improving sleep quality, increasing sleep efficiency, augmenting sleepmaintenance; increasing the value which is calculated from the time thata subject sleeps divided by the time that a subject is attempting tosleep; improving sleep initiation; decreasing sleep latency or onset(the time it takes to fall asleep); decreasing difficulties in fallingasleep; increasing sleep continuity; decreasing the number of awakeningsduring sleep; decreasing intermittent wakings during sleep; decreasingnocturnal arousals; decreasing the time spent awake following theinitial onset of sleep; increasing the total amount of sleep; reducingthe fragmentation of sleep; altering the timing, frequency or durationof REM sleep bouts; altering the timing, frequency or duration of slowwave (i.e. stages 3 or 4) sleep bouts; increasing the amount andpercentage of stage 2 sleep; promoting slow wave sleep; enhancingEEG-delta activity during sleep; decreasing nocturnal arousals,especially early morning awakenings; increasing daytime alertness;reducing daytime drowsiness; treating or reducing excessive daytimesleepiness; increasing satisfaction with the intensity of sleep;increasing sleep maintenance; idiopathic insomnia; sleep problems;insomnia, hypersomnia, idiopathic hypersomnia, repeatabilityhypersomnia, intrinsic hypersomnia, narcolepsy, interrupted sleep, sleepapnea, wakefulness, nocturnal myoclonus, REM sleep interruptions,jet-lag, shift workers' sleep disturbances, dyssomnias, night terror,insomnias associated with depression, emotional/mood disorders,Alzheimer's disease or cognitive impairment, as well as sleep walkingand enuresis, and sleep disorders which accompany aging; Alzheimer'ssundowning; conditions associated with circadian rhythmicity as well asmental and physical disorders associated with travel across time zonesand with rotating shift-work schedules, conditions due to drugs whichcause reductions in REM sleep as a side effect; fibromyalgia; syndromeswhich are manifested by non-restorative sleep and muscle pain or sleepapnea which is associated with respiratory disturbances during sleep;conditions which result from a diminished quality of sleep; increasinglearning; augmenting memory; increasing retention of memory; eatingdisorders associated with excessive food intake and complicationsassociated therewith, compulsive eating disorders, obesity (due to anycause, whether genetic or environmental), obesity-related disordersincluding overeating and bulimia nervosa, hypertension, diabetes,elevated plasma insulin concentrations and insulin resistance,dyslipidemias, hyperlipidemia, endometrial, breast, prostate and coloncancer, osteoarthritis, obstructive sleep apnea, cholelithiasis,gallstones, heart disease, abnormal heart rhythms and arrythmias,myocardial infarction, congestive heart failure, coronary heart disease,sudden death, stroke, polycystic ovary disease, craniopharyngioma, thePrader-Willi Syndrome, Frohlich's syndrome, GH-deficient subjects,normal variant short stature, Turner's syndrome, and other pathologicalconditions showing reduced metabolic activity or a decrease in restingenergy expenditure as a percentage of total fat-free mass, e.g, childrenwith acute lymphoblastic leukemia, metabolic syndrome, also known assyndrome X, insulin resistance syndrome, reproductive hormoneabnormalities, sexual and reproductive dysfunction, such as impairedfertility, infertility, hypogonadism in males and hirsutism in females,fetal defects associated with maternal obesity, gastrointestinalmotility disorders, such as obesity-related gastro-esophageal reflux,respiratory disorders, such as obesity-hypoventilation syndrome(Pickwickian syndrome), breathlessness, cardiovascular disorders,inflammation, such as systemic inflammation of the vasculature,arteriosclerosis, hypercholesterolemia, hyperuricaemia, lower back pain,gallbladder disease, gout, kidney cancer, increased anesthetic risk,reducing the risk of secondary outcomes of obesity, such as reducing therisk of left ventricular hypertrophy; diseases or disorders whereabnormal oscillatory activity occurs in the brain, including depression,migraine, neuropathic pain, Parkinson's disease, psychosis andschizophrenia, as well as diseases or disorders where there is abnormalcoupling of activity, particularly through the thalamus; enhancingcognitive function; enhancing memory; increasing memory retention;increasing immune response; increasing immune function; hot flashes;night sweats; extending life span; schizophrenia; muscle-relateddisorders that are controlled by the excitation/relaxation rhythmsimposed by the neural system such as cardiac rhythm and other disordersof the cardiovascular system; conditions related to proliferation ofcells such as vasodilation or vasorestriction and blood pressure;cancer; cardiac arrhythmia; hypertension; congestive heart failure;conditions of the genital/urinary system; disorders of sexual functionand fertility; adequacy of renal function; responsivity to anesthetics;mood disorders, such as depression or more particularly depressivedisorders, for example, single episodic or recurrent major depressivedisorders and dysthymic disorders, or bipolar disorders, for example,bipolar I disorder, bipolar II disorder and cyclothymic disorder, mooddisorders due to a general medical condition, and substance-induced mooddisorders; anxiety disorders including acute stress disorder,agoraphobia, generalized anxiety disorder, obsessive-compulsivedisorder, panic attack, panic disorder, post-traumatic stress disorder,separation anxiety disorder, social phobia, specific phobia,substance-induced anxiety disorder and anxiety due to a general medicalcondition; acute neurological and psychiatric disorders such as cerebraldeficits subsequent to cardiac bypass surgery and grafting, stroke,ischemic stroke, cerebral ischemia, spinal cord trauma, head trauma,perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage;Huntington's Chorea; amyotrophic lateral sclerosis; multiple sclerosis;ocular damage; retinopathy; cognitive disorders; idiopathic anddrug-induced Parkinson's disease; muscular spasms and disordersassociated with muscular spasticity including tremors, epilepsy,convulsions; cognitive disorders including dementia (associated withAlzheimer's disease, ischemia, trauma, vascular problems or stroke, HIVdisease, Parkinson's disease, Huntington's disease, Pick's disease,Creutzfeldt-Jacob disease, perinatal hypoxia, other general medicalconditions or substance abuse); delirium, amnestic disorders or agerelated cognitive decline; schizophrenia or psychosis includingschizophrenia (paranoid, disorganized, catatonic or undifferentiated),schizophreniform disorder, schizoaffective disorder, delusionaldisorder, brief psychotic disorder, shared psychotic disorder, psychoticdisorder due to a general medical condition and substance-inducedpsychotic disorder; substance-related disorders and addictive behaviors(including substance-induced delirium, persisting dementia, persistingamnestic disorder, psychotic disorder or anxiety disorder; tolerance,addictive feeding, dependence or withdrawal from substances includingalcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants,nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics);movement disorders, including akinesias and akinetic-rigid syndromes(including Parkinson's disease, drug-induced parkinsonism,postencephalitic parkinsonism, progressive supranuclear palsy, multiplesystem atrophy, corticobasal degeneration, parkinsonism-ALS dementiacomplex and basal ganglia calcification), chronic fatigue syndrome,fatigue, including Parkinson's fatigue, multiple sclerosis fatigue,fatigue caused by a sleep disorder or a circadian rhythm disorder,medication-induced parkinsonism (such as neuroleptic-inducedparkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acutedystonia, neuroleptic-induced acute akathisia, neuroleptic-inducedtardive dyskinesia and medication-induced postural tremor), Gilles de laTourette's syndrome, epilepsy, and dyskinesias [including tremor (suchas rest tremor, essential tremor, postural tremor and intention tremor),chorea (such as Sydenham's chorea, Huntington's disease, benignhereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-inducedchorea and hemiballism), myoclonus (including generalised myoclonus andfocal myoclonus), tics (including simple tics, complex tics andsymptomatic tics), restless leg syndrome and dystonia (includinggeneralised dystonia such as iodiopathic dystonia, drug-induceddystonia, symptomatic dystonia and paroxymal dystonia, and focaldystonia such as blepharospasm, oromandibular dystonia, spasmodicdysphonia, spasmodic torticollis, axial dystonia, dystonic writer'scramp and hemiplegic dystonia); attention deficit/hyperactivity disorder(ADHD); conduct disorder; migraine (including migraine headache);urinary incontinence; substance tolerance, substance withdrawal(including, substances such as opiates, nicotine, tobacco products,alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.);psychosis; schizophrenia; anxiety (including generalized anxietydisorder, panic disorder, and obsessive compulsive disorder); mooddisorders (including depression, mania, bipolar disorders); trigeminalneuralgia; hearing loss; tinnitus; neuronal damage including oculardamage; retinopathy; macular degeneration of the eye; emesis; brainedema; pain, including acute and chronic pain states, severe pain,intractable pain, inflammatory pain, neuropathic pain, post-traumaticpain, bone and joint pain (osteoarthritis), repetitive motion pain,dental pain, cancer pain, myofascial pain (muscular injury,fibromyalgia), perioperative pain (general surgery, gynecological),chronic pain, neuropathic pain, post-traumatic pain, trigeminalneuralgia, migraine and migraine headache.

Thus, in specific embodiments the present invention provides methodsfor: enhancing the quality of sleep; augmenting sleep maintenance;increasing REM sleep; increasing stage 2 sleep; decreasing fragmentationof sleep patterns; treating insomnia; enhancing cognition; increasingmemory retention; treating or controlling obesity; treating orcontrolling depression; treating, controlling, ameliorating or reducingthe risk of epilepsy, including absence epilepsy; treating orcontrolling pain, including neuropathic pain; treating or controllingParkinson's disease; treating or controlling psychosis; or treating,controlling, ameliorating or reducing the risk of schizophrenia, in amammalian patient in need thereof which comprises administering to thepatient a therapeutically effective amount of a compound of the presentinvention.

The subject compounds are further useful in a method for the prevention,treatment, control, amelioration, or reduction of risk of the diseases,disorders and conditions noted herein. The dosage of active ingredientin the compositions of this invention may be varied, however, it isnecessary that the amount of the active ingredient be such that asuitable dosage form is obtained. The active ingredient may beadministered to patients (animals and human) in need of such treatmentin dosages that will provide optimal pharmaceutical efficacy. Theselected dosage depends upon the desired therapeutic effect, on theroute of administration, and on the duration of the treatment. The dosewill vary from patient to patient depending upon the nature and severityof disease, the patient's weight, special diets then being followed by apatient, concurrent medication, and other factors which those skilled inthe art will recognize. Generally, dosage levels of between 0.0001 to 10mg/kg. of body weight daily are administered to the patient, e.g.,humans and elderly humans, to obtain effective antagonism of orexinreceptors. The dosage range will generally be about 0.5 mg to 1.0 g. perpatient per day which may be administered in single or multiple doses.In one embodiment, the dosage range will be about 0.5 mg to 500 mg perpatient per day; in another embodiment about 0.5 mg to 200 mg perpatient per day; and in yet another embodiment about 5 mg to 50 mg perpatient per day. Pharmaceutical compositions of the present inventionmay be provided in a solid dosage formulation such as comprising about0.5 mg to 500 mg active ingredient, or comprising about 1 mg to 250 mgactive ingredient. The pharmaceutical composition may be provided in asolid dosage formulation comprising about 1 mg, 5 mg, 10 mg, 25 mg, 50mg, 100 mg, 200 mg or 250 mg active ingredient. For oral administration,the compositions may be provided in the form of tablets containing 1.0to 1000 milligrams of the active ingredient, such as 1, 5, 10, 15, 20,25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and1000 milligrams of the active ingredient for the symptomatic adjustmentof the dosage to the patient to be treated. The compounds may beadministered on a regimen of 1 to 4 times per day, such as once or twiceper day.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of the present invention or the other drugs may have utility,where the combination of the drugs together are safer or more effectivethan either drug alone. Such other drug(s) may be administered, by aroute and in an amount commonly used therefor, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition in unit dosage form containingsuch other drugs and the compound of the present invention iscontemplated. However, the combination therapy may also includestherapies in which the compound of the present invention and one or moreother drugs are administered on different overlapping schedules. It isalso contemplated that when used in combination with one or more otheractive ingredients, the compounds of the present invention and the otheractive ingredients may be used in lower doses than when each is usedsingly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of the present invention. Theabove combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds.

Likewise, compounds of the present invention may be used in combinationwith other drugs that are used in the prevention, treatment, control,amelioration, or reduction of risk of the diseases or conditions forwhich compounds of the present invention are useful. Such other drugsmay be administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound of the presentinvention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention is contemplated. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention.

The weight ratio of the compound of the compound of the presentinvention to the second active ingredient may be varied and will dependupon the effective dose of each ingredient. Generally, an effective doseof each will be used. Thus, for example, when a compound of the presentinvention is combined with another agent, the weight ratio of thecompound of the present invention to the other agent will generallyrange from about 1000:1 to about 1:1000, such as about 200:1 to about1:200. Combinations of a compound of the present invention and otheractive ingredients will generally also be within the aforementionedrange, but in each case, an effective dose of each active ingredientshould be used. In such combinations the compound of the presentinvention and other active agents may be administered separately or inconjunction. In addition, the administration of one element may be priorto, concurrent to, or subsequent to the administration of otheragent(s).

The compounds of the present invention may be administered incombination with other compounds which are known in the art to be usefulfor enhancing sleep quality and preventing and treating sleep disordersand sleep disturbances, including e.g., sedatives, hypnotics,anxiolytics, antipsychotics, antianxiety agents, antihistamines,benzodiazepines, barbiturates, cyclopyrrolones, GABA agonists, 5HT-2antagonists including 5HT-2A antagonists and 5HT-2A/2C antagonists,histamine antagonists including histamine H3 antagonists, histamine H3inverse agonists, imidazopyridines, minor tranquilizers, melatoninagonists and antagonists, melatonergic agents, other orexin antagonists,orexin agonists, prokineticin agonists and antagonists,pyrazolopyrimidines, T-type calcium channel antagonists,triazolopyridines, and the like, such as: adinazolam, allobarbital,alonimid, alprazolam, amitriptyline, amobarbital, amoxapine,armodafinil, APD-125, bentazepam, benzoctamine, brotizolam, bupropion,busprione, butabarbital, butalbital, capromorelin, capuride,carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide,clomipramine, clonazepam, cloperidone, clorazepate, clorethate,clozapine, conazepam, cyprazepam, desipramine, dexclamol, diazepam,dichloralphenazone, divalproex, diphenhydramine, doxepin, EMD-281014,eplivanserin, estazolam, eszopiclone, ethchlorynol, etomidate, fenobam,flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam,gaboxadol, glutethimide, halazepam, hydroxyzine, ibutamoren, imipramine,indiplon, lithium, lorazepam, lormetazepam, LY-156735, maprotiline,MDL-100907, mecloqualone, melatonin, mephobarbital, meprobamate,methaqualone, methyprylon, midaflur, midazolam, modafinil, nefazodone,NGD-2-73, nisobamate, nitrazepam, nortriptyline, oxazepam, paraldehyde,paroxetine, pentobarbital, perlapine, perphenazine, phenelzine,phenobarbital, prazepam, promethazine, propofol, protriptyline,quazepam, ramelteon, reclazepam, roletamide, secobarbital, sertraline,suproclone, TAK-375, temazepam, thioridazine, tiagabine, tracazolate,tranylcypromaine, trazodone, triazolam, trepipam, tricetamide,triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam,venlafaxine, zaleplon, zolazepam, zopiclone, zolpidem, and saltsthereof, and combinations thereof, and the like, or the compound of thepresent invention may be administered in conjunction with the use ofphysical methods such as with light therapy or electrical stimulation.

In another embodiment, the subject compound may be employed incombination with other compounds which are known in the art, eitheradministered separately or in the same pharmaceutical compositions,include, but are not limited to: insulin sensitizers including (i) PPARγantagonists such as glitazones (e.g. ciglitazone; darglitazone;englitazone; isaglitazone (MCC-555); pioglitazone; rosiglitazone;troglitazone; tularik; BRL49653; CLX-0921; 5-BTZD), GW-0207, LG-100641,and LY-300512, and the like); (iii) biguanides such as metformin andphenformin; (b) insulin or insulin mimetics, such as biota, LP-100,novarapid, insulin detemir, insulin lispro, insulin glargine, insulinzinc suspension (lente and ultralente); Lys-Pro insulin, GLP-1 (73-7)(insulintropin); and GLP-1 (7-36)-NH₂); (c) sulfonylureas, such asacetohexamide; chlorpropamide; diabinese; glibenclamide; glipizide;glyburide; glimepiride; gliclazide; glipentide; gliquidone; glisolamide;tolazamide; and tolbutamide; (d) α-glucosidase inhibitors, such asacarbose, adiposine; camiglibose; emiglitate; miglitol; voglibose;pradimicin-Q; salbostatin; CKD-711; MDL-25,637; MDL-73,945; and MOR 14,and the like; (e) cholesterol lowering agents such as (i) HMG-CoAreductase inhibitors (atorvastatin, itavastatin, fluvastatin,lovastatin, pravastatin, rivastatin, rosuvastatin, simvastatin, andother statins), (ii) bile acid absorbers/sequestrants, such ascholestyramine, colestipol, dialkylaminoalkyl derivatives of across-linked dextran; Colestid®; LoCholest®, and the like, (ii)nicotinyl alcohol, nicotinic acid or a salt thereof, (iii)proliferator-activater receptor a agonists such as fenofibric acidderivatives (gemfibrozil, clofibrate, fenofibrate and benzafibrate),(iv) inhibitors of cholesterol absorption such as stanol esters,beta-sitosterol, sterol glycosides such as tiqueside; and azetidinonessuch as ezetimibe, and the like, and (acyl CoA:cholesterolacyltransferase (ACAT)) inhibitors such as avasimibe, and melinamide,(v) anti-oxidants, such as probucol, (vi) vitamin E, and (vii)thyromimetics; (f) PPARα agonists such as beclofibrate, benzafibrate,ciprofibrate, clofibrate, etofibrate, fenofibrate, and gemfibrozil; andother fibric acid derivatives, such as Atromid®, Lopid® and Tricor®, andthe like, and PPARα agonists as described in WO 97/36579 by Glaxo; (g)PPARδ agonists; (h) PPAR α/δ agonists, such as muraglitazar, and thecompounds disclosed in U.S. Pat. No. 6,414,002; and (i) anti-obesityagents, such as (1) growth hormone secretagogues, growth hormonesecretagogue receptor agonists/antagonists, such as NN703, hexarelin,MK-0677, SM-130686, CP-424,391, L-692,429, and L-163,255; (2) proteintyrosine phosphatase-1B (PTP-1B) inhibitors; (3) cannabinoid receptorligands, such as cannabinoid CB₁ receptor antagonists or inverseagonists, such as rimonabant (Sanofi Synthelabo), AMT-251, and SR-14778and SR 141716A (Sanofi Synthelabo), SLV-319 (Solvay), BAY 65-2520(Bayer); (4) anti-obesity serotonergic agents, such as fenfluramine,dexfenfluramine, phentermine, and sibutramine; (5) β3-adrenoreceptoragonists, such as AD9677/TAK677 (Dainippon/Takeda), CL-316,243, SB418790, BRL-37344, L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243,Trecadrine, Zeneca D7114, SR 59119A; (6) pancreatic lipase inhibitors,such as orlistat (Xenical®), Triton WR1339, RHC80267, lipstatin,tetrahydrolipstatin, teasaponin, diethylumbelliferyl phosphate; (7)neuropeptide Y1 antagonists, such as BIBP3226, J-115814, BIBO 3304,LY-357897, CP-671906, GI-264879A; (8) neuropeptide Y5 antagonists, suchas GW-569180A, GW-594884A, GW-587081X, GW-548118X, FR226928, FR 240662,FR252384, 1229U91, GI-264879A, CGP71683A, LY-377897, PD-160170,SR-120562A, SR-120819A and JCF-104; (9) melanin-concentrating hormone(MCH) receptor antagonists; (10) melanin-concentrating hormone 1receptor (MCH1R) antagonists, such as T-226296 (Takeda); (11)melanin-concentrating hormone 2 receptor (MCH2R) agonist/antagonists;(12) orexin receptor antagonists, such as SB-334867-A, and thosedisclosed in patent publications herein; (13) serotonin reuptakeinhibitors such as fluoxetine, paroxetine, and sertraline; (14)melanocortin agonists, such as Melanotan II; (15) other Mc4r(melanocortin 4 receptor) agonists, such as CHIR86036 (Chiron),ME-10142, and ME-10145 (Melacure), CHIR86036 (Chiron); PT-141, and PT-14(Palatin); (16) 5HT-2 agonists; (17) 5HT2C (serotonin receptor 2C)agonists, such as BVT933, DPCA37215, WAY161503, R-1065; (18) galaninantagonists; (19) CCK agonists; (20) CCK-A (cholecystokinin-A) agonists,such as AR-R 15849, GI 181771, JMV-180, A-71378, A-71623 and SR14613;(22) corticotropin-releasing hormone agonists; (23) histamine receptor-3(H3) modulators; (24) histamine receptor-3 (H3) antagonists/inverseagonists, such as hioperamide, 3-(1H-imidazol-4-yl)propylN-(4-pentenyl)carbamate, clobenpropit, iodophenpropit, imoproxifan,GT2394 (Gliatech), and O-[3-(1H-imidazol-4-yl)propanol]-carbamates; (25)β-hydroxy steroid dehydrogenase-1 inhibitors (β-HSD-1); 26) PDE(phosphodiesterase) inhibitors, such as theophylline, pentoxifylline,zaprinast, sildenafil, amrinone, milrinone, cilostamide, rolipram, andcilomilast; (27) phosphodiesterase-3B (PDE3B) inhibitors; (28) NE(norepinephrine) transport inhibitors, such as GW 320659, despiramine,talsupram, and nomifensine; (29) ghrelin receptor antagonists; (30)leptin, including recombinant human leptin (PEG-OB, Hoffman La Roche)and recombinant methionyl human leptin (Amgen); (31) leptin derivatives;(32) BRS3 (bombesin receptor subtype 3) agonists such as[D-Phe6,beta-Ala11,Phe13,Nle14]Bn(6-14) and[D-Phe6,Phe13]Bn(6-13)propylamide, and those compounds disclosed inPept. Sci. 2002 August; 8(8): 461-75); (33) CNTF (Ciliary neurotrophicfactors), such as GI-181771 (GlaxoSmithKline), SR146131 (SanofiSynthelabo), butabindide, PD170,292, and PD 149164 (Pfizer); (34) CNTFderivatives, such as axokine (Regeneron); (35) monoamine reuptakeinhibitors, such as sibutramine; (36) UCP-1 (uncoupling protein-1), 2,or 3 activators, such as phytanic acid,4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1-propenyl]benzoicacid (TTNPB), retinoic acid; (37) thyroid hormone β agonists, such asKB-2611 (KaroBioBMS); (38) FAS (fatty acid synthase) inhibitors, such asCerulenin and C75; (39) DGAT1 (diacylglycerol acyltransferase 1)inhibitors; (40) DGAT2 (diacylglycerol acyltransferase 2) inhibitors;(41) ACC2 (acetyl-CoA carboxylase-2) inhibitors; (42) glucocorticoidantagonists; (43) acyl-estrogens, such as oleoyl-estrone, disclosed indel Mar-Grasa, M. et al., Obesity Research, 9:202-9 (2001); (44)dipeptidyl peptidase IV (DP-IV) inhibitors, such as isoleucinethiazolidide, valine pyrrolidide, NVP-DPP728, LAF237, MK-431, P93/01,TSL 225, TMC-2A/2B/2C, FE 999011, P9310/K364, VIP 0177, SDZ 274-444;(46) dicarboxylate transporter inhibitors; (47) glucose transporterinhibitors; (48) phosphate transporter inhibitors; (49) Metformin(Glucophage®); and (50) Topiramate (Topimax®); and (50) peptide YY, PYY3-36, peptide YY analogs, derivatives, and fragments such as BIM-43073D,BIM-43004C (Olitvak, D. A. et al., Dig. Dis. Sci. 44(3):643-48 (1999));(51) Neuropeptide Y2 (NPY2) receptor agonists such NPY3-36, N acetyl[Leu(28,31)] NPY 24-36, TASP-V, andcyclo-(28/32)-Ac-[Lys28-Glu32]-(25-36)-pNPY; (52) Neuropeptide Y4 (NPY4)agonists such as pancreatic peptide (PP), and other Y4 agonists such as1229U91; (54) cyclooxygenase-2 inhibitors such as etoricoxib, celecoxib,valdecoxib, parecoxib, lumiracoxib, BMS347070, tiracoxib or JTE522,ABT963, CS502 and GW406381, and pharmaceutically acceptable saltsthereof; (55) Neuropeptide Y1 (NPY1) antagonists such as BIBP3226,J-115814, BIBO 3304, LY-357897, CP-671906, GI-264879A; (56) Opioidantagonists such as nalmefene (Revex®), 3-methoxynaltrexone, naloxone,naltrexone; (57) 11β HSD-1 (11-beta hydroxy steroid dehydrogenasetype 1) inhibitor such as BVT 3498, BVT 2733; (58) aminorex; (59)amphechloral; (60) amphetamine; (61) benzphetamine; (62)chlorphentermine; (63) clobenzorex; (64) cloforex; (65) clominorex; (66)clortermine; (67) cyclexedrine; (68) dextroamphetamine; (69)diphemethoxidine, (70) N-ethylamphetamine; (71) fenbutrazate; (72)fenisorex; (73) fenproporex; (74) fludorex; (75) fluminorex; (76)furfurylmethylamphetamine; (77) levamfetamine; (78) levophacetoperane;(79) mefenorex; (80) metamfepramone; (81) methamphetamine; (82)norpseudoephedrine; (83) pentorex; (84) phendimetrazine; (85)phenmetrazine; (86) picilorex; (87) phytopharm 57; and (88) zonisamide.

In another embodiment, the subject compound may be employed incombination with an anti-depressant or anti-anxiety agent, includingnorepinephrine reuptake inhibitors (including tertiary amine tricyclicsand secondary amine tricyclics), selective serotonin reuptake inhibitors(SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors ofmonoamine oxidase (RIMAs), serotonin and noradrenaline reuptakeinhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists,α-adrenoreceptor antagonists, neurokinin-1 receptor antagonists,atypical anti-depressants, benzodiazepines, 5-HT_(1A) agonists orantagonists, especially 5-HT_(1A) partial agonists, and corticotropinreleasing factor (CRF) antagonists. Specific agents include:amitriptyline, clomipramine, doxepin, imipramine and trimipramine;amoxapine, desipramine, maprotiline, nortriptyline and protriptyline;fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid,phenelzine, tranylcypromine and selegiline; moclobemide: venlafaxine;aprepitant; bupropion, lithium, nefazodone, trazodone and viloxazine;alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam,halazepam, lorazepam, oxazepam and prazepam; buspirone, flesinoxan,gepirone and ipsapirone, and pharmaceutically acceptable salts thereof.

In another embodiment, the subject compound may be employed incombination with anti-Alzheimer's agents; beta-secretase inhibitors;gamma-secretase inhibitors; growth hormone secretagogues; recombinantgrowth hormone; HMG-CoA reductase inhibitors; NSAID's includingibuprofen; vitamin E; anti-amyloid antibodies; CB-1 receptor antagonistsor CB-1 receptor inverse agonists; antibiotics such as doxycycline andrifampin; N-methyl-D-aspartate (NMDA) receptor antagonists, such asmemantine; cholinesterase inhibitors such as galantamine, rivastigmine,donepezil, and tacrine; growth hormone secretagogues such as ibutamoren,ibutamoren mesylate, and capromorelin; histamine H3 antagonists; AMPAagonists; PDE IV inhibitors; GABAA inverse agonists; or neuronalnicotinic agonists.

In another embodiment, the subject compound may be employed incombination with sedatives, hypnotics, anxiolytics, antipsychotics,antianxiety agents, cyclopyrrolones, imidazopyridines,pyrazolopyrimidines, minor tranquilizers, melatonin agonists andantagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2antagonists, and the like, such as: adinazolam, allobarbital, alonimid,alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam,benzoctamine, brotizolam, bupropion, busprione, butabarbital,butalbital, capuride, carbocloral, chloral betaine, chloral hydrate,chlordiazepoxide, clomipramine, clonazepam, cloperidone, clorazepate,clorethate, clozapine, cyprazepam, desipramine, dexclamol, diazepam,dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam,ethchlorvynol, etomidate, fenobam, flunitrazepam, flurazepam,fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam,hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline,mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone,midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline,oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine,perphenazine, phenelzine, phenobarbital, prazepam, promethazine,propofol, protriptyline, quazepam, reclazepam, roletamide, secobarbital,sertraline, suproclone, temazepam, thioridazine, tracazolate,tranylcypromaine, trazodone, triazolam, trepipam, tricetamide,triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam,venlafaxine, zaleplon, zolazepam, zolpidem, and salts thereof, andcombinations thereof, and the like, or the subject compound may beadministered in conjunction with the use of physical methods such aswith light therapy or electrical stimulation.

In another embodiment, the subject compound may be employed incombination with levodopa (with or without a selective extracerebraldecarboxylase inhibitor such as carbidopa or benserazide),anticholinergics such as biperiden (optionally as its hydrochloride orlactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMTinhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2aadenosine receptor antagonists, cholinergic agonists, NMDA receptorantagonists, serotonin receptor antagonists and dopamine receptoragonists such as alentemol, bromocriptine, fenoldopam, lisuride,naxagolide, pergolide and pramipexole. It will be appreciated that thedopamine agonist may be in the form of a pharmaceutically acceptablesalt, for example, alentemol hydrobromide, bromocriptine mesylate,fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate.Lisuride and pramipexol are commonly used in a non-salt form.

In another embodiment, the subject compound may be employed incombination with acetophenazine, alentemol, benzhexol, bromocriptine,biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam,fenoldopam, fluphenazine, haloperidol, levodopa, levodopa withbenserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine,molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide,pramipexole, risperidone, sulpiride, tetrabenazine, trihexyphenidyl,thioridazine, thiothixene or trifluoperazine.

In another embodiment, the subject compound may be employed incombination with a compound from the phenothiazine, thioxanthene,heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine andindolone classes of neuroleptic agent. Suitable examples ofphenothiazines include chlorpromazine, mesoridazine, thioridazine,acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitableexamples of thioxanthenes include chlorprothixene and thiothixene. Anexample of a dibenzazepine is clozapine. An example of a butyrophenoneis haloperidol. An example of a diphenylbutylpiperidine is pimozide. Anexample of an indolone is molindolone. Other neuroleptic agents includeloxapine, sulpiride and risperidone. It will be appreciated that theneuroleptic agents when used in combination with thesubject compound maybe in the form of a pharmaceutically acceptable salt, for example,chlorpromazine hydrochloride, mesoridazine besylate, thioridazinehydrochloride, acetophenazine maleate, fluphenazine hydrochloride,flurphenazine enathate, fluphenazine decanoate, trifluoperazinehydrochloride, thiothixene hydrochloride, haloperidol decanoate,loxapine succinate and molindone hydrochloride. Perphenazine,chlorprothixene, clozapine, haloperidol, pimozide and risperidone arecommonly used in a non-salt form.

In another embodiment, the subject compound may be employed incombination with an anoretic agent such as aminorex, amphechloral,amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex,clominorex, clortermine, cyclexedrine, dexfenfluramine,dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine,fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex,fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane,mazindol, mefenorex, metamfepramone, methamphetamine,norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine,phentermine, phenylpropanolamine, picilorex and sibutramine; selectiveserotonin reuptake inhibitor (SSRI); halogenated amphetaminederivatives, including chlorphentermine, cloforex, clortermine,dexfenfluramine, fenfluramine, picilorex and sibutramine; andpharmaceutically acceptble salts thereof.

In another embodiment, the subject compound may be employed incombination with an opiate agonist, a lipoxygenase inhibitor, such as aninhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as acyclooxygenase-2 inhibitor, an interleukin inhibitor, such as aninterleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitricoxide or an inhibitor of the synthesis of nitric oxide, a non-steroidalantiinflammatory agent, or a cytokine-suppressing antiinflammatoryagent, for example with a compound such as acetaminophen, asprin,codiene, fentanyl, ibuprofen, indomethacin, ketorolac, morphine,naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl,sunlindac, tenidap, and the like. Similarly, the subject compound may beadministered with a pain reliever; a potentiator such as caffeine, anH2-antagonist, simethicone, aluminum or magnesium hydroxide; adecongestant such as phenylephrine, phenylpropanolamine, pseudophedrine,oxymetazoline, ephinephrine, naphazoline, xylometazoline,propylhexedrine, or levo-desoxy-ephedrine; an antiitussive such ascodeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; adiuretic; and a sedating or non-sedating antihistamine.

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals such as mice, rats, horses, cattle,sheep, dogs, cats, monkeys, etc., the compounds of the invention areeffective for use in humans.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

Pharmaceutical compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. Compositions for oral use may also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example peanut oil, liquidparaffin, or olive oil. Aqueous suspensions contain the active materialsin admixture with excipients suitable for the manufacture of aqueoussuspensions. Oily suspensions may be formulated by suspending the activeingredient in a suitable oil. Oil-in-water emulsions may also beemployed. Dispersible powders and granules suitable for preparation ofan aqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Pharmaceutical compositions of thepresent compounds may be in the form of a sterile injectable aqueous oroleagenous suspension. The compounds of the present invention may alsobe administered in the form of suppositories for rectal administration.For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of the present invention may be employed.The compounds of the present invention may also be formulated foradministered by inhalation. The compounds of the present invention mayalso be administered by a transdermal patch by methods known in the art.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsare made according to procedures known in the art or as illustratedherein. The following abbreviations are used herein: Me: methyl; Et:ethyl; t-Bu: teat-butyl; Ar: aryl; Ph: phenyl; Bn: benzyl; Ac: acetyl;THF: tetrahydrofuran; DEAD: diethylazodicarboxylate; DBAD:di-tert-butylazodicarboxylate; DIPEA: N,N-diisopropylethylamine; DMSO:dimethylsulfoxide; EDC: N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide;HOBT: hydroxybenzotriazole hydrate; Boc: tert-butyloxy carbonyl; Et₃N:triethylamine; DCM: dichloromethane; DCE: dichloroethane; BSA: bovineserum albumin; TFA: trifluoracetic acid; DMF: N,N-dimethylformamide;MTBE: methyl tert-butyl ether;SOCl₂: thionyl chloride; CDI: carbonyldiimidazole; rt: room temperature; HPLC: high performance liquidchromatography; T3P: 1-propylphosphonic anhydride. The compounds of thepresent invention can be prepared in a variety of fashions.

In some cases the final product may be further modified, for example, bymanipulation of substituents. These manipulations may include, but arenot limited to, reduction, oxidation, alkylation, acylation, andhydrolysis reactions which are commonly known to those skilled in theart. In some cases the order of carrying out the foregoing reactionschemes and examples nmay be varied to facilitate the reaction or toavoid unwanted reaction products. The following examples are provided sothat the invention might be more fully understood. These examples areillustrative only and should not be construed as limiting the inventionin any way.

EXAMPLE A

Ethyl 2-(2-cyanoethyl)-3-oxobutanoate (A-1)

A solution of solid sodium metal (450 mg, 19.75 mmol) in EtOH at 30° C.was treated with ethyl acetoacetate (103 g, 790 mmol) maintainingtemperature. Then acrylonitrile (41.9 g, 790 mmol) was added dropwiseover 15 minutes. The reaction was capped and stirred for 4 hours. Thesolution was concentrated and the resulting solid was dissolved in 20 mLof water and 3 mL of acetic acid, and washed with 50 mL of DCM. Theorganic layer was dried over Na₂SO₄ and concentrated to an oil.Distillation was performed under reduced pressure (0.5 mm) with a bathtemperature of 80° C. Fractions were collected and concentrated toprovide A-1 as a colorless oil. Data for A-1: LC/MS: m/z (M+H)=183.87found; 183.20 required

Ethyl-2-methylpipridine-3-carboxalate (A-2)

A solution of A-1 (5.65 g, 30.8 mmol) in acetic acid (50 mL) was treatedwith 5 mol % platinum oxide (350 mg, 1.5 mmol). The Parr bottle wasevacuated and backfilled with H₂ (g) three times and stirred under a H₂(g) atmosphere (45 psi, recharged 4 times) at 22° C. for 3 h. Themixture was filtered though Celite and the filter cake was washed withEtOH. The filtrate was concentrated to yield product with a ˜9:1cis:trans diastereomer ratio. NMR analysis indicated the cis-isomer hasa methyl doublet at 1.25 ppm, and the trans-isomer at 1.07 ppm. Thismaterial was diluted with 50 mL EtOH, treated with sodium ethoxide (1.04g, 15.4 mmol), heated to 50° C., and stirred at this temperatureovernight. The reaction was monitored for completion using thediagnostic NMR data. The mixture was cooled to 22° C., neutralized to pH7 with conc. HCl, filtered through celite and the filtrate wasconcentrated. The residue was suspended in EtOH and filtered again. Theresulting filtrate was concentrated to yield A-3 (˜9:1 trans:cis). Datafor A-3: LC/MS: m/z (M+H)=172.92 found; 172.24 required

2-methylpipridin-3-yl]methanol (A-3)

A solution of A-2 (3 g, 17.52 mmol) in 40 mL THF at 0° C. was treatedwith a 2M solution of LAH in THF (21.9 mL, 43.8 mmol). The reaction wasslowly warmed to room temperature with stirring and allowed to stir atroom temperature for 12 h. The reaction was then cooled to −10° C. andwas carefully quenched with 1.7 mL water, then 1 7 mL 15% NaOH, followedby an additional 5 mL of water. A portion of Na₂SO₄ was added and themixture was stirred for 1 h before being filtered through celite. Thefiltrate was concentrated to provide A-3 as a colorless oil. Data forA-3: LC/MS: m/z (M+H)=130.11 found; 130.20 required

5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl chloride (A-4)

A solution of 2-iodo-5-methylbenzoic acid (4.0 g, 15.3 mmol) in DMF (10mL) was treated with 1,2,3-triazole (2.1 g, 30.5 mmol), CsCO₃ (9.95 g,30.5 mmol), CuI (0.145 g, 0.76 mmol) andtrans-N,N′-dimethylcyclohexane-1,2-diamine (0.43 g, 3.05 mmol). Themixture was heated at 120° C. for 10 min in a microwave reactor. Thereaction was cooled to room temperature, diluted with water, and washedwith EtOAc. The aqueous phase was acidified with 1N HCl and extractedwith EtOAc. The organic layer was dried over Na₂SO₄, filtered andconcentrated. The residue was purified by gradient elution on SiO₂ (0 to10% MeOH in DCM with 0.1% AcOH) to give the faster eluting2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid A-2, followed by theundesired regioisomer isomer, 1-(2H-1,2,3-triazol-2-yl)-5-methylbenzoicacid. A solution of the acid (3.56 g, 17.52 mmol) in 150 mL of DCM wasstirred and cooled to 0° C. The solution was treated with oxalylchloride (1.9 mL, 21.9 mmol) and DMF (68 μL, 0.878 mmol). The solutionwas slowly warmed to room temperature and stirred overnight. Solvent wasconcentrated and the resulting solid was azetroped with DCM andconcentrated to provide A-4 as a yellow solid.

2-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}methanol(A-5)

A solution of the amine A-3 (2.03 g, 15.71 mmol) in DCM (100 ml) wastreated with TEA (5.47 ml, 39.3 mmol). The mixture was stirred at 22° C.while A-4 (3.7 g, 17.18 mmol) was added. The solution was stirred for 2hours at room temperature. The mixture was partitioned between EtOAc andwater. The organic phase was dried over Na₂SO₄, filtered andconcentrated. The crude material was purified by gradient elution onsilica gel (0 to 100% EtOAc in Hex) to yield A-5 as a white solid. Datafor A-5: LC/MS: rt=1.55 min; m/z (M+H)=315.28 found; 315.38 required

2-2-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}methoxy)pyridine(A-6)

A solution of A-5 (110 mg, 0.350 mmol) in 2 mL of DMF was treated with2-fluoropyridine (37.3 mg, 0.384 mmol) and 60% NaH (28 mg, 0.70 mmol).The mixture was heated to 50° C. and stirred for 2 hours. The reactionwas then partitioned between EtOAc and water. The organic phase wasdried over Na₂SO₄, filtered and concentrated. The crude material waspurified by gradient elution on silica gel (0 to 100% EtOAc in Hex) toyield A-6 as a white solid. Data for A-6: LC/MS: rt=1.88 min; m/z(M+H)=392.25 found; 392.47 required. HRMS (APCI): m/z (M+H)=392.4698found; 392.4692 required.

Table 1

The following compounds were prepared using the foregoing methodology,but substituting the appropriately substituted reagent, as described inthe foregoing Reaction Schemes and Examples. The requisite startingmaterials were commercially available, described in the literature orreadily synthesized by one skilled in the art of organic synthesiswithout undue experimentation. Some final products were purified byflash chromatography (SiO₂; EtOAc/hexanesor MeOH/CH₂Cl₂) and wereisolated as the free-base; alternately, some products were purified byreverse phase HPLC (CH₃CN/H₂O containing 0.1% TFA as a modifier) andisolated as the TFA salt, in which case the masses reported and foundare for the free-base. Alternatively, fractions containing the productcould be basified with NaHCO₃ and extracted with EtOAc, dried overNa₂SO₄, and concentrated to provide the free-base.

HRMS m/z Cpd Structure Name (M + H) A-7

5-bromo-2-({2-methyl-1-[5- methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3- yl}methoxy)pyridine 470.1184 found, 470.1186required. A-8

1-({2-methyl-1-[5-methyl- 2-(2H-1,2,3-triazol-2- yl)benzoyl]piperidin-3-yl}methoxy)isoquinoline 442.3791 found, 442.3795 required. A-9

2-bromo-6-({2-methyl-1-[5- methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3- yl}methoxy)pyridine 470.3619 found, 470.3609required. A-10

4-({2-methyl-1-[5-methyl- 2-(2H-1,2,3-triazol-2- yl)benzoyl]piperidin-3-yl}methoxy)quinoline 442.2236 found, 442.2238 required.

Table 2

Table 2 shows representative data for the compounds of the Examples asorexin-1 receptor (OX1R) and/or orexin-2 receptor (OX2R) antagonists asdetermined by the foregoing assays.

Cmpd Structure OX1R K_(i) (nM) OX2R K_(i) (nM) A-6

1.0 nM 39 nM A-7

1.1 nM 6.4 nM A-8

0.5 nM 2.1 nM A-9

2.7 nM 7.5 nM A-10

0.6 nM 2.6 nM

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.

1. A compound of the formula I:

wherein: A is selected from the group consisting of phenyl, napthyl andheteroaryl; B is selected from the group consisting of phenyl, napthyland heteroaryl; R^(1a), R^(1b) and R^(1c) may be absent if the valencyof A does not permit such substitution and are independently selectedfrom the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl,(4) —(C═O)_(m)—O_(n)—C₁₋₆alkyl, where m is 0 or 1, n is 0 or 1 (whereinif m is 0 or n is 0, a bond is present) and where the alkyl isunsubstituted or substituted with one or more substituents selected fromR¹³, (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl isunsubstituted or substituted with one or more substituents selected fromR¹³, (6) —(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted orsubstituted with one or more substituents selected from R¹³, (7)—(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted orsubstituted with one or more substituents selected from R¹³, (8)—(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-napthyl, where the phenyl ornapthyl is unsubstituted or substituted with one or more substituentsselected from R¹³, (9) —(C═O)_(m)—O_(n)-heterocycle, where theheterocycle is unsubstituted or substituted with one or moresubstituents selected from R¹³, (10) —(C═O)_(m)—NR¹⁰R¹¹, wherein R¹⁰ andR¹¹ are independently selected from the group consisting of: (a)hydrogen, (b) C₁₋₆alkyl, which is unsubstituted or substituted with R¹³,(c) C₃₋₆alkenyl, which is unsubstituted or substituted with R¹³, (d)C₃₋₆alkynyl, which is unsubstituted or substituted with R¹³, (e)C₃₋₆cycloalkyl which is unsubstituted or substituted with R¹³, (f)phenyl, which is unsubstituted or substituted with R¹³, and (g)heterocycle, which is unsubstituted or substituted with R¹³, (11)—S(O)₂—NR¹⁰R¹¹, (12) —S(O)_(q)—R¹², where q is 0, 1 or 2 and where R¹²is selected from the definitions of R¹⁰ and R¹¹, (13) —CO₂H, (14) —CN,and (15) —NO₂; R^(2a), R^(2b) and R^(2c) may be absent if the valency ofB does not permit such substitution and are independently selected fromthe group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4)—(C═O)_(m)—O_(n)—C₁₋₆alkyl, where the alkyl is unsubstituted orsubstituted with one or more substituents selected from R¹³, (5)—(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is unsubstitutedor substituted with one or more substituents selected from R¹³, (6)—(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted orsubstituted with one or more substituents selected from R¹³, (7)—(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted orsubstituted with one or more substituents selected from R¹³, (8)—(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-napthyl, where the phenyl ornapthyl is unsubstituted or substituted with one or more substituentsselected from R¹³, (9) —(C═O)_(m)—O_(n)-heterocycle, where theheterocycle is unsubstituted or substituted with one or moresubstituents selected from R¹³, (10) —(C═O)_(m)—NR¹⁰R¹¹, (11)—S(O)₂—NR¹⁰R¹¹, (12) —S(O)_(q)—R¹², (13) —CO₂H, (14) —CN, and (15) —NO₂;R³ is C₁₋₆alkyl or C₃₋₆cycloalkyl, which is unsubstituted or substitutedwith one or more substituents selected from R¹³; R⁴ and R⁵ areindependently selected from hydrogen and C₁₋₆alkyl, which isunsubstituted or substituted with one or more substituents selected fromR¹³, or R⁴ and R⁵ may be joined together to form a C₃₋₆cycloalkyl withthe carbon atom to which they are attached, where the cycloalkyl isunsubstituted or substituted with one or more substituents selected fromR¹³; R¹³ is selected from the group consisting of: (1) halogen, (2)hydroxyl, (3) —(C═O)_(m)—O_(n)—C₁₋₆alkyl, where the alkyl isunsubstituted or substituted with one or more substituents selected fromR¹⁴, (4) —O_(n)—(C₁₋₃)perfluoroalkyl, (5)—(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is unsubstitutedor substituted with one or more substituents selected from R¹⁴, (6)—(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted orsubstituted with one or more substituents selected from R¹⁴, (7)—(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted orsubstituted with one or more substituents selected from R¹⁴, (8)—(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-napthyl, where the phenyl ornapthyl is unsubstituted or substituted with one or more substituentsselected from R¹⁴, (9) —(C═O)_(m)—O_(n)-heterocycle, where theheterocycle is unsubstituted or substituted with one or moresubstituents selected from R¹⁴, (10) —(C═O)_(m)—NR¹⁰R¹¹, (11)—S(O)₂—NR¹⁰R¹¹, (12) —S(O)_(q)—R¹², (13) —CO₂H, (14) —CN, and (15) —NO₂;R¹⁴ is selected from the group consisting of: (1) hydroxyl, (2) halogen,(3) C₁₋₆alkyl, (4) —C₃₋₆cycloalkyl, (5) —O—C₁₋₆alkyl, (6)—O(C═O)—C₁₋₆alkyl, (7) —NH—C₁₋₆alkyl, (8) phenyl, (9) heterocycle, (10)—CO₂H, and (11) —CN; or a pharmaceutically acceptable salt thereof. 2.The compound of claim 1 of the formula Ia:

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim1 of the formula Ib:

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim1 wherein A is selected from the group consisting of: phenyl, pyrazolyl,and thiazolyl.
 5. The compound of claim 1 wherein A is phenyl.
 6. Thecompound of claim 1 wherein B is independently selected from the groupconsisting of: (1) phenyl, (2) quinoline, (3) isoquinoline, (4)benzoxazole, (5) thienopyridine, (6) pyridine, (7) furan, (8)naphthyridine, (9) benzothiazole, and (10) pyrimidine.
 7. The compoundof claim 6 wherein B is selected from the group consisting of quinoline,isoquinoline and pyridine.
 8. The compound of claim 1 wherein R^(1a),R^(1b) and R^(1c) are independently selected from the group consistingof: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) C₁₋₆alkyl, which isunsubstituted or substituted with halogen, hydroxyl, phenyl or napthyl,(5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with halogen,hydroxyl or phenyl, (6) heteroaryl, wherein heteroaryl is selected fromtriazolyl, oxazolyl, pyrrolyl, imidazolyl, indolyl, pyridyl, andpyrimidinyl, which is unsubstituted or substituted with halogen,hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂, (7) phenyl, which isunsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,—O—C₁₋₆alkyl or —NO₂, (8) —O-phenyl, which is unsubstituted orsubstituted with halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂, and(9) —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl), which is unsubstitutedor substituted with halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂.9. The compound of claim 8 wherein R^(1a), R^(1b) and R^(1c) areindependently selected from the group consisting of: (1) hydrogen, (2)halogen, (3) C₁₋₆alkyl, (4) triazolyl, (5) oxazolyl, (6) pyrimidinyl,and (7) phenyl.
 10. The compound of claim 9 wherein R^(1c) is hydrogenand R^(1a) and R^(1b) are independently selected from the groupconsisting of: (1) hydrogen, (2) chloro, (3) fluroro, (4) methyl, (5)triazolyl, (6) oxazolyl, (7) pyrimidinyl, and (8) phenyl.
 11. Thecompound of claim 1 wherein R^(2a), R^(2b) and R^(2c) are independentlyselected from the group consisting of: (1) hydrogen, (2) halogen, (3)hydroxyl, (4) C₁₋₆alkyl, which is unsubstituted or substituted withhalogen, hydroxyl or phenyl or napthyl, (5) —O—C₁₋₆alkyl, which isunsubstituted or substituted with halogen, hydroxyl or phenyl, (6)heteroaryl, wherein heteroaryl is selected from pyrrolyl, imidazolyl,indolyl, pyridyl, and pyrimidinyl, which is unsubstituted or substitutedwith halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂, (7) phenyl,which is unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,—O—C₁₋₆alkyl or —NO₂, (8) —O-phenyl, which is unsubstituted orsubstituted with halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂, and(9) —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl), which is unsubstitutedor substituted with halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂.12. The compound of claim 11 wherein R^(2a), R^(2b) and R^(2c) areindependently selected from the group consisting of: (1) hydrogen, (2)halogen, (3) C₁₋₆alkyl, which is unsubstituted or substituted withhalogen, (4) —O—C₁₋₆alkyl, which is unsubstituted or substituted withhalogen, and (5) —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl), which isunsubstituted or substituted with halogen.
 13. The compound of claim 12wherein R^(2c) is hydrogen, and R^(2a) and R^(2b) are independentlyselected from the group consisting of: (1) hydrogen, (2) chloro, (3)fluoro, (4) bromo, (5) methoxy, (6) t-butoxy, (7) difluoromethyl, and(8) trifluoromethyl.
 14. The compound of claim 1 wherein R³ isC₁₋₆alkyl.
 15. The compound of claim 14 wherein R³ is methyl.
 16. Thecompound of claim 1 wherein R⁴ is hydrogen or C₁₋₆alkyl and R⁵ ishydrogen or C₁₋₆alkyl.
 17. The compound of claim 16 wherein R⁴ ishydrogen and R⁵ is hydrogen.
 18. A compound which is selected from thegroup consisting of:2-2-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}methoxy)pyridine;5-bromo-2-({2-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}methoxy)pyridine;1-({2-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}methoxy)isoquinoline;2-bromo-6-({2-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}methoxy)pyridine;and4-({2-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]piperidin-3-yl}methoxy)quinoline;or a pharmaceutically acceptable salt thereof.
 19. A pharmaceuticalcomposition which comprises an inert carrier and a compound of claim 1or a pharmaceutically acceptable salt thereof.
 20. (canceled) 21.(canceled)
 22. (canceled)
 23. A method for treating insomnia in amammalian patient in need thereof which comprises administering to thepatient a therapeutically effective amount of the compound of claim 1 ora pharmaceutically acceptable salt thereof.
 24. (canceled)